Instructions for Octra injection solution 0.1 mg/ml ampoule 1 ml No. 5
Composition
active ingredient: octreotide;
1 ml of solution contains octreotide acetate 0.1 mg in terms of 100% substance;
excipients: mannitol (E 421), sodium bicarbonate, lactic acid, water for injections.
Dosage form
Solution for injection.
Main physicochemical properties: transparent colorless solution.
Pharmacotherapeutic group
Hormone preparations for systemic use, except sex hormones and insulin. Hypothalamic and pituitary hormones and their analogues. Hypothalamic hormones. Somatostatin and analogues. Octreotide.
ATX code H01C B02.
Pharmacological properties
Pharmacodynamics.
Octra® is a synthetic octapeptide, which is a derivative of the natural hormone somatostatin and has similar pharmacological effects, but a much longer duration of action. The drug inhibits pathologically increased secretion of growth hormone (GH), as well as peptides and serotonin, which are produced in the gastro-entero-pancreatic endocrine system.
In animals, octreotide is a more potent inhibitor of growth hormone, glucagon, and insulin release than somatostatin, with greater selectivity for growth hormone and glucagon inhibition.
In healthy individuals, octreotide inhibits: growth hormone secretion stimulated by arginine, exercise and insulin hypoglycemia; secretion of insulin, glucagon, gastrin and other peptides of the gastro-entero-pancreatic endocrine system stimulated by food intake, as well as secretion of insulin and glucagon stimulated by arginine; secretion of thyrotropin induced by thyrotropin-releasing hormone.
Unlike somatostatin, octreotide inhibits growth hormone more than insulin, and its administration is not accompanied by rebound hypersecretion of hormones (i.e., growth hormone in patients with acromegaly).
In patients with acromegaly, octreotide reduces plasma concentrations of GH and insulin-like growth factor-1 (IGF-1). GH suppression of 50% or more is observed in 90% of patients; a decrease in plasma GH levels to less than 5 ng/mL is achieved in approximately half of patients. In most patients with acromegaly, octreotide markedly reduces the severity of symptoms such as headache, hyperhidrosis, fatigue, joint pain, paresthesia, and carpal tunnel syndrome. In patients with pituitary adenomas secreting GH, treatment with octreotide may result in tumor shrinkage.
In patients with functional endocrine tumors of the gastrointestinal tract and pancreas, octreotide, due to its various endocrine effects, affects a number of clinical features of the disease. Clinical and symptomatic improvement is observed in patients who still have symptoms related to the tumors despite previous treatment, which may include surgical treatment methods, hepatic artery embolization and various chemotherapy, such as the use of streptozotocin and 5-fluorouracil.
In carcinoid tumors, the use of octreotide can lead to a decrease in the severity of symptoms such as hot flashes and diarrhea, which in many cases is accompanied by a decrease in plasma serotonin concentration and urinary excretion of 5-hydroxyindoleacetic acid.
In tumors characterized by hyperproduction of vasoactive intestinal peptide (VIP), the use of octreotide leads in most patients to a decrease in severe secretory diarrhea, which is characteristic of this condition, which, in turn, improves the patient's quality of life. At the same time, there is a decrease in concomitant electrolyte imbalance, such as hypokalemia, which allows for the abolition of enteral and parenteral administration of fluids and electrolytes. In some patients, tumor growth slows down or stops and even reduces its size, especially liver metastases. Clinical improvement is usually accompanied by a decrease (even to normal) in the concentration of vasoactive intestinal peptide in the blood plasma.
In glucagonomas, the use of octreotide in most cases leads to a marked reduction in the necrotizing migratory rashes that are characteristic of this condition. Octreotide does not have any significant effect on the mild diabetes mellitus that is often observed in glucagonomas and usually does not lead to a decrease in the need for insulin or oral hypoglycemic drugs. In patients suffering from diarrhea, octreotide helps to reduce it, which is accompanied by an increase in body weight. When using octreotide, a rapid decrease in plasma glucagon concentration is often noted, but this effect is not maintained with prolonged treatment. At the same time, symptomatic improvement remains stable for a long time.
In patients with insulinomas, octreotide reduces the level of immunoreactive insulin in the blood. This effect, however, may be short-lived - about 2 hours. In patients with operable tumors, octreotide may provide restoration and maintenance of normoglycemia in the preoperative period. In patients with inoperable benign and malignant tumors, glycemic control may improve without a concomitant long-term decrease in insulin levels in the blood.
In patients with tumors that overproduce growth hormone-releasing factor (GH-RH-RH) (somatoliberinomas), octreotide reduces the severity of acromegaly symptoms. This is apparently due to inhibition of the secretion of GH-RH and growth hormone itself. Pituitary hypertrophy may subsequently be reduced.
In refractory diarrhea in patients with acquired immunodeficiency syndrome (AIDS), the use of octreotide leads to complete or partial normalization of stool in approximately 1/3 of patients suffering from diarrhea that is not controlled by adequate therapy with antimicrobial and/or antidiarrheal agents.
In patients undergoing pancreatic surgery, the use of octreotide during and after surgery reduces the incidence of typical postoperative complications (e.g. pancreatic fistulas, abscesses, sepsis, postoperative acute pancreatitis).
In patients with esophageal and gastric variceal bleeding, octreotide, in combination with specific treatment (e.g., sclerotherapy), resulted in more effective control of bleeding and prevention of early rebleeding, reduced transfusion requirements, and improved 5-day survival. Although the exact mechanism of action of octreotide is not known, it is thought to reduce organ blood flow by inhibiting vasoactive hormones such as VIP and glucagon.
Pharmacokinetics.
After subcutaneous administration, octreotide is rapidly and completely absorbed. The maximum plasma concentration of the drug is reached within 30 minutes. Binding to plasma proteins is 65%. Binding of octreotide to blood cells is extremely insignificant. The volume of distribution is 0.27 l/kg. Total clearance is 160 ml/min. The half-life after subcutaneous injection of the drug is 100 minutes. After intravenous administration, the drug is eliminated in two phases with half-lives of 10 and 90 minutes, respectively. Most of the administered peptide dose is excreted in the feces, approximately 32% is excreted unchanged in the urine. Impaired renal function does not affect the total exposure (area under the concentration-time curve) of octreotide administered subcutaneously. Elimination capacity may be reduced by 30% in patients with cirrhosis, but this does not apply to patients with hepatic steatosis.
Clinical characteristics.
Indication
· Acromegaly - to control the main manifestations of the disease and reduce the levels of GH and IGF-1 in the blood plasma in cases where there is no sufficient effect from surgical treatment and radiotherapy. Octra® is also indicated for the treatment of patients with acromegaly who have refused surgery or have contraindications to it, as well as for short-term treatment in the intervals between courses of radiotherapy until its effect is fully developed.
· Relief of symptoms associated with endocrine tumors of the gastrointestinal tract (GI) and pancreas:
- carcinoid tumors with the presence of carcinoid syndrome;
- VIPomas (tumors characterized by hyperproduction of vasoactive intestinal peptide);
- glucagonomas;
- gastrinomas/Zollinger-Ellison syndrome – usually in combination with histamine H2 receptor antagonists or proton pump inhibitors;
- insulinomas (for hypoglycemia control in the preoperative period, as well as for maintenance therapy);
- somatoliberinomas (tumors characterized by hyperproduction of growth hormone releasing factor).
Octra® is not an anticancer drug, and its use cannot lead to a cure for this category of patients.
· Prevention of complications after pancreatic surgery.
· Stopping bleeding and preventing recurrence of bleeding from esophageal varices in patients with liver cirrhosis (in combination with specific therapeutic measures, for example, endoscopic sclerosing therapy).
Contraindication
Known hypersensitivity to octreotide or other components of the drug.
Interaction with other medicinal products and other types of interactions
Dosage adjustments of medications such as beta-blockers, calcium channel blockers, or medications to control fluid and electrolyte balance may be necessary when octreotide is used concomitantly.
Dosage adjustments of insulin and hypoglycemic drugs may be necessary when octreotide is used concomitantly.
Octreotide has been shown to reduce the intestinal absorption of cyclosporine and slow the absorption of cimetidine.
Limited published data suggest that somatostatin analogues may reduce the metabolic clearance of substances metabolised by cytochrome P450 enzymes, possibly due to inhibition of GH secretion. Since such an effect cannot be excluded for octreotide, caution should be exercised when using other drugs metabolised primarily by CYP 3A4 and with a narrow therapeutic index (e.g. quinidine, terfenadine).
Application features
Subcutaneous injections
Patients who self-administer the drug by subcutaneous injection should receive precise instructions from their doctor or nurse.
To reduce discomfort at the injection site, it is recommended to bring the solution to room temperature before injection. Repeated injections at the same site within a short period of time should be avoided.
Ampoules should be opened only before administration, and any remaining product should be discarded.
Intravenous infusions
The diluted solution remains physically and chemically stable for at least 24 hours at a temperature not exceeding 25 °C.
General
Because pituitary tumors that secrete GH can sometimes enlarge, causing serious complications (e.g., narrowing of the visual fields), careful monitoring of all patients is essential. If there is evidence of tumor enlargement, alternative treatments should be considered.
The therapeutic effect of lowering GH levels and normalizing IGF-1 concentrations in women with acromegaly may potentially restore fertility. Women of childbearing potential should be advised to use adequate contraception during treatment with octreotide (see also section "Use during pregnancy and lactation").
Thyroid function (TSH and thyroid hormones) should be monitored in patients receiving long-term therapy with octreotide.
Liver function should be monitored during octreotide therapy.
Phenomena related to the cardiovascular system
Bradycardia has been commonly reported. Dose adjustments of medications such as beta-blockers, calcium channel blockers, and medications to control fluid and electrolyte balance may be necessary.
Phenomena related to the gallbladder
Octreotide inhibits cholecystokinin secretion, resulting in decreased gallbladder contractility and an increased risk of sludge syndrome and stone formation. Gallstones are observed in 15-30% of patients receiving octreotide. Overall, stone formation occurs in 5-20% of the population. Therefore, ultrasound examination of the gallbladder is recommended before initiating Octreotide therapy and approximately every 6-12 months during Octreotide treatment. The occurrence of gallstones in patients treated with octreotide was in most cases asymptomatic; in the event of clinical manifestations, cholelithiasis should be treated with bile acid preparations or by surgical intervention.
Endocrine tumors of the gastrointestinal tract and pancreas
During the treatment of endocrine tumors of the gastrointestinal tract and pancreas, a sudden loss of symptomatic control with Octra® may occasionally occur, accompanied by a rapid return of severe symptoms. If the drug is discontinued, symptoms may worsen or recur.
Glucose metabolism
Due to its inhibitory effect on growth hormone, glucagon and insulin, Octra® may impair glucose regulation. Postprandial glucose tolerance may be impaired and in some cases, persistent hyperglycemia may occur as a result of chronic administration of the drug. Hypoglycemia may also occur.
In patients with insulinomas, octreotide may increase the severity and prolong the duration of hypoglycemia due to its greater relative ability to suppress GH and glucagon secretion than insulin, and due to its short duration of insulin inhibition. These patients should be closely monitored during treatment with Octreotide and at each dose change. Apparent fluctuations in blood glucose concentrations may be reduced by more frequent administration of Octreotide in smaller doses.
The dependence of patients with type 1 diabetes mellitus on insulin or oral hypoglycemic agents can be reduced by the administration of Octra®. In patients without diabetes or with type 2 diabetes with partially intact insulin reserve, the administration of Octra® may lead to an increase in postprandial glycemia. Careful monitoring of glucose tolerance and antidiabetic treatment are recommended.
Bleeding from esophageal varices
Because bleeding from esophageal varices increases the risk of developing insulin-dependent diabetes mellitus and may alter insulin requirements in diabetic patients, adequate monitoring of blood glucose concentrations is mandatory.
In a 52-week toxicity study in rats, predominantly males, sarcomas were observed at the subcutaneous injection site only at the highest dose (approximately 8 times the maximum human dose based on body surface area). In a 52-week toxicity study in dogs, no hyperplastic or neoplastic lesions were observed at the subcutaneous injection site. There have been no reports of injection site tumours in patients treated with octreotide for up to 15 years. All information available to date suggests that the findings in rats are species-specific and have no relevance to human use.
Food
Octreotide may impair the absorption of dietary fats in some patients.
Reduced vitamin B12 levels and abnormal Schilling test results have been observed in some patients treated with octreotide. Patients with a history of vitamin B12 deficiency should have their vitamin B12 levels monitored during Octreotide therapy.
This medicinal product contains less than 1 mmol sodium/dose, i.e. essentially sodium-free.
Use during pregnancy or breastfeeding
Pregnancy
There are limited data (less than 300 outcomes) on octreotide treatment in pregnant women, but in approximately one third of cases the outcome of the pregnancy is unknown. Most reports have been received after post-marketing use of octreotide, and the proportion of pregnant women among patients with acromegaly was more than 50%. Most women received octreotide during the first trimester of pregnancy at doses of 100-1200 micrograms/day. Congenital disorders of the child have been reported in approximately 4% of pregnancies with an unknown outcome. In these cases, no relationship to octreotide was found.
Animal studies did not indicate direct or indirect harmful effects with respect to reproductive toxicity.
It is advisable to avoid the use of Octra® during pregnancy.
Lactation
Breastfeeding is not recommended during treatment with Octreotide®. It is not known whether octreotide is excreted in human milk. In animal studies, octreotide has been observed to be excreted in breast milk.
Fertility
It is not known whether octreotide affects human fertility. In the case of use of the drug by patients during pregnancy or breastfeeding, delayed testicular descent has been observed in male newborns. Although in experimental studies, octreotide did not affect fertility in male and female rats at doses up to 1 mg/kg body weight per day.
Ability to influence reaction speed when driving vehicles or other mechanisms
Octra® has no or negligible influence on the ability to drive and use machines. Patients should be advised to exercise caution when driving or operating machinery if they experience dizziness, asthenia/fatigue, or headache during treatment with Octra®.
Method of administration and doses
For intravenous administration, Octra® should be diluted with saline in a volume ratio of not less than 1:1 and not more than 1:9. Dilution of Octra® with glucose solution is not recommended.
In acromegaly, initially the drug is administered subcutaneously at 0.05–0.1 mg every 8 or 12 hours. In the future, the dose selection should be based on monthly determinations of GH and IGF-1 concentrations, analysis of clinical symptoms and tolerability of the drug (target hormone concentrations are: GH - less than 2.5 ng/ml, IGF-1 - within the normal range). For most patients, the optimal daily dose is 0.3 mg. The maximum daily dose is 1.5 mg, which should not be exceeded. In patients receiving a stable dose of Octra®, determination of GH concentration should be carried out every 6 months.
If within 3 months of treatment with Octreotide® there is no sufficient decrease in GH levels and improvement in the clinical picture of the disease, therapy should be discontinued.
In endocrine tumors of the gastrointestinal tract and pancreas, the drug is administered subcutaneously in an initial dose of 0.05 mg 1-2 times a day. Subsequently, depending on the achieved clinical effect, as well as the effect on the levels of hormones produced by the tumor (in the case of carcinoid tumors - on the urinary excretion of 5-hydroxyindoleacetic acid), the dose of the drug can be gradually increased to 0.1-0.2 mg 3 times a day. In exceptional cases, higher doses may be required.
Maintenance doses of the drug should be selected individually.
If no improvement occurs within one week of Octreotide treatment of carcinoid tumors, further therapy is not recommended.
The subcutaneous route of administration is recommended, however, in cases where a rapid clinical effect is required, such as carcinoid crises, the initial recommended dose of Octra® can be administered intravenously, using a bolus injection after dilution of the dose and monitoring of the heart rate.
To prevent complications after pancreatic surgery, the drug should be administered subcutaneously at a dose of 0.1 mg 3 times a day for the next 7 days, starting from the day of surgery (at least 1 hour before laparotomy).
In patients with cirrhosis and bleeding from gastric and esophageal varices, good tolerance to Octra® was noted when receiving a stable dose of the drug up to 50 mcg/h as a continuous intravenous infusion for 5 days.
Use in patients with renal impairment
Impaired renal function does not affect the overall exposure (area under the curve of drug concentration versus time (AUC)) of octreotide administered by subcutaneous injection. Therefore, no dose adjustment of Octreotide is required.
Use in patients with impaired liver function
In patients with cirrhosis of the liver, the half-life of the drug may increase, requiring adjustment of the maintenance dose.
Use in the elderly
There is no evidence of reduced tolerability or the need for dosage adjustment in elderly patients treated with Octreotide.
Children
The use of Octra® in children is contraindicated due to the lack of clinical experience.
Overdose
There are limited reports of accidental overdose with octreotide in adults and children. In adults, doses ranged from 2400 to 6000 micrograms/day when administered by continuous infusion (100 to 250 micrograms/hour) or subcutaneously (1500 micrograms three times a day). The following adverse events have been reported: arrhythmia, hypotension, cardiac arrest, cerebral hypoxia, pancreatitis, hepatic steatosis, diarrhea, weakness, somnolence, weight loss, hepatomegaly, and lactic acidosis.
For children, doses ranged from 50 to 3000 micrograms/day and were administered by continuous infusion (2.1 to 500 micrograms/hour) or subcutaneously (50 to 100 micrograms). The only adverse event was mild hyperglycemia.
No unexpected adverse events were observed in cancer patients receiving octreotide doses of 3000-30000 micrograms/day in divided doses subcutaneously.
Treatment: symptomatic.
Adverse reactions
The most common adverse reactions during treatment with octreotide include disorders of the gastrointestinal tract, nervous system, liver and gallbladder, metabolism and trophic disorders.
The most commonly reported adverse reactions in clinical trials with octreotide were diarrhea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycemia, and constipation. Other commonly reported adverse reactions included dizziness, local pain, gallstones, thyroid dysfunction (e.g., decreased thyroid-stimulating hormone, decreased total T4, and decreased free T4), loose stools, impaired glucose tolerance, vomiting, asthenia, and hypoglycemia.
The information on the adverse reactions listed below was obtained during clinical trials of octreotide.
Gastrointestinal: diarrhea, abdominal pain, nausea, constipation, flatulence, dyspepsia, vomiting, abdominal distension, steatorrhea, loose stools, discoloration of feces.
From the hepatobiliary system: cholelithiasis, cholecystitis, gallstones, hyperbilirubinemia.
From the nervous system: headache, dizziness.
Endocrine system: hypothyroidism, thyroid dysfunction (e.g. decreased thyroid-stimulating hormone, decreased total T4, decreased free T4).
Metabolism and nutrition: hyperglycemia, hypoglycemia, impaired glucose tolerance, anorexia, dehydration.
General disorders and administration site conditions: injection site pain, asthenia.
Laboratory tests: increased transaminase levels.
Skin and subcutaneous tissue disorders: itching, rash, alopecia.
Respiratory system: dyspnea.
From the cardiovascular system: bradycardia, tachycardia.
Adverse reactions to octreotide reported in the post-marketing period
Immune system disorders: anaphylaxis, allergy/hypersensitivity reactions.
Skin and subcutaneous tissue disorders: urticaria.
Hepatobiliary system: acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice.
Cardiovascular system: arrhythmia.
Laboratory abnormalities: increased alkaline phosphatase, increased gammaglutamyltransferase.
Description of selected adverse reactions
Gastrointestinal disorders
In rare cases, gastrointestinal adverse reactions may resemble acute intestinal obstruction – progressive abdominal distension, severe epigastric pain, abdominal tenderness, and muscle “tension.”
It is known that with continued treatment with the drug, the frequency of adverse reactions from the gastrointestinal tract decreases.
Gastrointestinal side effects can be reduced by not eating before or immediately after subcutaneous administration of octreotide; it is recommended to administer the drug between meals or at bedtime.
Local reactions
Pain or a tingling, itching, or burning sensation at the site of subcutaneous injection, with redness and swelling, rarely lasts longer than 15 minutes. Local discomfort may be reduced by bringing the solution to room temperature before injection, or by injecting a smaller volume of a more concentrated solution.
Although fecal fat excretion may increase, there is no evidence that long-term treatment with octreotide can lead to the development of trophic deficiencies due to malabsorption.
Pancreatic disorders
Acute pancreatitis has been reported very rarely. This phenomenon usually occurs within the first hours or days of subcutaneous administration of octreotide and resolves after discontinuation of the drug. In addition, pancreatitis secondary to cholelithiasis may occur in patients receiving long-term subcutaneous octreotide.
Isolated cases of biliary colic have been observed after abrupt drug withdrawal in patients with acromegaly who developed gallstones in the gallbladder.
Cardiovascular system disorders
In patients with acromegaly and carcinoid syndrome, ECG changes such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave enlargement, and nonspecific ST-T interval changes have been observed. The relationship between these events and octreotide acetate has not been established, since many of these patients have underlying cardiac disease (see section 4.4).
Expiration date
3 years.
Do not use the drug after the expiration date indicated on the package.
Storage conditions
Store in the original packaging at a temperature of 2 ° C to 8 ° C. Do not freeze.
Keep out of reach of children.
Packaging
1 ml in an ampoule. 5 ampoules in a pack.
Vacation category
According to the recipe.
Producer
PJSC "Farmak".
Location of the manufacturer and its business address
Ukraine, 04080, Kyiv, Frunze St., 74.
